linoleic-acid and Asthma

Asthma is the most common chronic disease within the paediatric population. Although it is multifactorial, its onset may be linked to early-life exposures with subsequent impact on immune system development. Microbial and dietary metabolic products have been implicated in the development and exacerbation of paediatric asthma. Linoleic acid is the most common omega-6 polyunsaturated fatty acid in the Western diet. In this review, we summarise the literature regarding the involvement of linoleic acid in the development of and its impact on existing paediatric asthma. First, we summarise the existing knowledge surrounding the relationship between human microbial metabolism and allergic diseases in children. Next, we examine cellular or animal model-based mechanistic studies that investigated the impact of dietary- and microbial-derived linoleic acid metabolites on asthma. Finally, we review the literature investigating the impact of linoleic acid metabolites on the development and exacerbation of childhood asthma. While there is conflicting evidence, there is growing support for a role of linoleic acid in the onset and pathophysiology of asthma. We recommend that additional cellular, animal, and longitudinal studies are performed that target linoleic acid and its metabolites.

Topics: Animals; Asthma; Child; Humans; Linoleic Acid

The last two decades have seen an increase in the prevalence of asthma, eczema, and allergic rhinitis in developed countries. This increase has been paralleled by a fall in the consumption of saturated fat and an increase in the amount of polyunsaturated fat in the diet. This is due to a reduction in the consumption of animal fat and an increase in the use of margarine and vegetable oils containing omega-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid. There is also evidence for a decrease in the consumption of oily fish which contain omega-3 PUFAs, such as eicosapentaenoic acid. In a number of countries, there are social class and regional differences in the prevalence of allergic disease, which are associated with differences in the consumption of PUFAs. Linoleic acid is a precursor of arachidonic acid, which can be converted to prostaglandin E2 (PGE2), whereas eicosapentaenoic acid inhibits the formation of PGE2. PGE2 acts on T-lymphocytes to reduce the formation of interferon-gamma (IFN-gamma) without affecting the formation of interleukin-4 (IL-4). This may lead to the development of allergic sensitization, since IL-4 promotes the synthesis of immunoglobulin E (IgE), whereas IFN-gamma has the opposite effect. Changes in the diet may explain the increase in the prevalence of asthma, eczema and allergic rhinitis. The effects of diet may be mediated through an increase in the synthesis of prostaglandin E2 which in turn can promote the formation of immunoglobulin E.

Topics: Animals; Arachidonic Acids; Asthma; Developed Countries; Dietary Fats; Dietary Fats, Unsaturated; Dinoprostone; Eczema; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Feeding Behavior; Fishes; Humans; Immunoglobulin E; Interferon-gamma; Interleukin-4; Linoleic Acid; Linoleic Acids; Margarine; Plant Oils; Prevalence; Respiratory Hypersensitivity; Rhinitis; Social Class; T-Lymphocytes

We investigated in a clinical setting whether increased intake of linoleic acid alters respiratory function in 26 mild asthmatics. Subjects completed a 16-week-dietary intervention comprising 8 weeks eating an enriched n-6 polyunsaturated fat diet (9.2% energy from linoleic acid) and consuming either a high monounsaturated or saturated fat diet in a random cross-over resign for 8 weeks. Neither FEV1 nor PC20 values changed significantly after increased linoleic acid consumption when compared with the other diets. Increased consumption of linoleic acid caused a 20% rise (p < or = 0.01) in plasma linoleic acid, a 38% decrease (p < or = 0.01) in plasma eicosapentaenoic acid, but no change in arachidonic acid. There were no changes in symptom scores or bronchodilator use.

Topics: Asthma; Cross-Over Studies; Fatty Acids; Female; Forced Expiratory Volume; Histamine; Humans; Linoleic Acid; Male; Margarine; Middle Aged; Peak Expiratory Flow Rate

PUFAs may influence the risk of asthma; however, long-term prospective studies including objective biomarkers of PUFA intake are lacking.. The objective was to investigate the role of dietary intake and plasma concentrations of n-3 and n-6 (ω-3 and ω-6) PUFAs in childhood and adolescence for the development of asthma and lung function up to young adulthood.. The study included participants from the Swedish prospective birth cohort BAMSE. Dietary intake of PUFAs was calculated from FFQs (n = 1992) and plasma proportions of PUFAs were measured in phospholipids (n = 831). We analyzed the n-3 PUFA α-linolenic acid (ALA; 18:3n-3); the sum of very-long-chain (VLC) n-3 PUFAs: EPA (20:5n-3), DHA (22:6n-3), and docosapentaenoic acid (22:5n-3); and the n-6 PUFAs linoleic acid (LA; 18:2n-6) and arachidonic acid (AA; 20:4n-6). Asthma was assessed by questionnaires at 8, 16, and 24 y and lung function was measured by spirometry at 24 y.. A high (≥median) self-reported dietary intake of LA at 8 y and AA at 16 y was associated with increased risk of prevalent asthma at 24 y (OR: 1.41; 95% CI: 1.10, 1.82 and OR: 1.32; 95% CI: 1.02, 1.70, respectively). In contrast, plasma proportions of ALA, ∑VLC n-3 PUFAs, and AA at 8 y, as well as LA at 16 y, were inversely associated with prevalent asthma at 24 y (e.g., OR: 0.55; 95% CI: 0.38, 0.81 for ∑VLC n-3 PUFAs). No consistent associations were observed with lung function.. High dietary intake of certain n-6 PUFAs in childhood or adolescence may be associated with increased risk of asthma up to young adulthood, whereas dietary biomarkers of certain n-3 and n-6 PUFAs in plasma may be associated with decreased risk. Thus, the role of diet compared with altered metabolism of PUFAs needs further investigation to improve dietary preventive strategies for asthma.

Topics: Adolescent; Adult; Asthma; Biomarkers; Eating; Fatty Acids, Omega-3; Humans; Linoleic Acid; Lung; Prospective Studies; Young Adult

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30-74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and β-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.

Topics: 3-Hydroxybutyric Acid; Adaptor Proteins, Signal Transducing; Adiposity; Adult; Aged; Asthma; Blood Cell Count; Body Mass Index; Cell Cycle Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Linoleic Acid; Lipid Metabolism; Lipids; Male; Middle Aged; Obesity; Pulmonary Disease, Chronic Obstructive

Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n-6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials.. To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma.. We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)-control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality.. Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (-0.03; 95% CI: -0.061, -0.004) and lower neutrophil count (-0.04; 95% CI: -0.057, -0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses.. LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

Topics: Asthma; Case-Control Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Inflammation; Linoleic Acid; Multivariate Analysis; Polymorphism, Single Nucleotide; United Kingdom

Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Disease Models, Animal; Drug Resistance; Epithelial Cells; Humans; Hypersensitivity; Linoleic Acid; Lipid Metabolism; Mice; NF-kappa B; Receptors, Glucocorticoid; Respiratory Mucosa; Steroids

Oxylipins are oxidised fatty acids that can exert lipid mediator functions in inflammation, and several oxylipins derived from arachidonic acid are linked to asthma. This study quantified oxylipin profiles in different regions of the lung to obtain a broad-scale characterisation of the allergic asthmatic inflammation in relation to healthy individuals. Bronchoalveolar lavage fluid (BALF), bronchial wash fluid and endobronchial mucosal biopsies were collected from 16 healthy and 16 mildly allergic asthmatic individuals. Inflammatory cell counts, immunohistochemical staining and oxylipin profiling were performed. Univariate and multivariate statistics were employed to evaluate compartment-dependent and diagnosis-dependent oxylipin profiles in relation to other measured parameters. Multivariate modelling showed significantly different bronchial wash fluid and BALF oxylipin profiles in both groups (R(2)Y[cum]=0.822 and Q(2)[cum]=0.759). Total oxylipin concentrations and five individual oxylipins, primarily from the lipoxygenase (LOX) pathway of arachidonic and linoleic acid, were elevated in bronchial wash fluid from asthmatics compared to that from healthy controls, supported by immunohistochemical staining of 15-LOX-1 in the bronchial epithelium. No difference between the groups was found among BALF oxylipins. In conclusion, bronchial wash fluid and BALF contain distinct oxylipin profiles, which may have ramifications for the study of respiratory diseases. Specific protocols for sampling proximal and distal airways separately should be employed for lipid mediator studies.

Topics: Adolescent; Adult; Arachidonic Acid; Asthma; Biopsy; Bronchoalveolar Lavage Fluid; Bronchoscopy; Case-Control Studies; Exhalation; Female; Gene Expression Regulation; Healthy Volunteers; Humans; Hypersensitivity; Inflammation; Linoleic Acid; Lipids; Male; Nitric Oxide; Oxylipins; Young Adult

Airway epithelial injury is the hallmark of various respiratory diseases, but its mechanisms remain poorly understood. While 13-S-hydroxyoctadecadienoic acid (13-S-HODE) is produced in high concentration during mitochondrial degradation in reticulocytes little is known about its role in asthma pathogenesis. Here, we show that extracellular 13-S-HODE induces mitochondrial dysfunction and airway epithelial apoptosis. This is associated with features of severe airway obstruction, lung remodeling, increase in epithelial stress related proinflammatory cytokines and drastic airway neutrophilia in mouse. Further, 13-S-HODE induced features are attenuated by inhibiting Transient Receptor Potential Cation Channel, Vanilloid-type 1 (TRPV1) both in mouse model and human bronchial epithelial cells. These findings are relevant to human asthma, as 13-S-HODE levels are increased in human asthmatic airways. Blocking of 13-S-HODE activity or disruption of TRPV1 activity attenuated airway injury and asthma mimicking features in murine allergic airway inflammation. These findings indicate that 13-S-HODE induces mitochondrial dysfunction and airway epithelial injury.

Topics: Animals; Asthma; Calcium; Disease Models, Animal; Extracellular Space; Fatty Acids, Unsaturated; Gene Knockdown Techniques; Humans; Linoleic Acid; Mice; Mice, Inbred BALB C; Mitochondria; Neutrophils; Respiratory Mucosa; Species Specificity; TRPV Cation Channels

It has been suggested that atopic dermatitis (AD) is associated with impaired delta-6 desaturase activity and the subsequent altered composition of n-6 essential fatty acids (EFAs).. To investigate whether n-6 EFA deficiency accounts for AD by affecting transepidermal water loss or the immune response.. Serum levels of n-6 EFAs were measured using gas chromatography-mass spectrometry in a well-defined group of 35 children with AD (IgE level >150 U/mL); 35 age-matched children with allergic rhinitis, asthma, or both (IgE level >150 U/mL); and 31 nonatopic controls (IgE level <100 U/mL). Skin barrier function was evaluated by measuring transepidermal water loss and severity of AD by computing the Scoring Atopic Dermatitis (SCORAD) index.. Atopic children had higher levels of linoleic acid (LA) and lower levels of its metabolites. Furthermore, gamma-linolenic acid to LA and dihommo-gamma-linolenic acid to LA ratios were significantly reduced in atopic patients. Transepidermal water loss and the SCORAD index were negatively correlated with serum levels of LA metabolites. There was no correlation between the SCORAD index and IgE level (P = .51) or between n-6 EFA concentrations and IgE level (P > .10).. Deficits in n-6 EFAs were correlated with the severity of AD by affecting skin barrier function and cutaneous inflammation. The link between impaired n-6 EFA metabolism and IgE level could not be defined.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Arachidonic Acid; Asthma; Child; Child, Preschool; Dermatitis, Atopic; Epidermis; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Immunoglobulin E; Linoleic Acid; Lipids; Male; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Water; Water Loss, Insensible

Epidemiological evidence suggests that increased dietary omega-6 and reduced omega-3 fatty acid intake, may have contributed to the rising prevalence of asthma, but these hypotheses have not been tested in studies comparing both dietary intake and objective measures of polyunsaturated fatty acids.. To assess whether a higher intake of omega-6 or a lower intake of omega-3 fatty acids increases the risk of asthma, by measuring dietary fatty acid intake by a food frequency questionnaire (FFQ) and erythrocyte membrane fatty acids, as an objective biomarker of intake.. We have compared individual fatty acid intake estimated by FFQ and by mass spectrometry of fasting erythrocyte cell membranes in 89 cases of asthma and 89 community-matched controls.. The odds of asthma were increased in relation to intake of the omega-3 fatty acids eicosapentaenoic acid (odds ratio (OR) for difference between the 25th and 75th centiles of intake= 1.89, 95% CI 1.15-3.11) and docosahexaenoic acid (OR = 2.11, 95% CI 1.19-3.74). There was no evidence of any difference in erythrocyte membrane levels of omega-3 fatty acids, while the odds of asthma were reduced in relation to linoleic acid (omega-6) membrane levels (OR = 0.45, 95% CI 0.21-0.95).. These findings suggest that dietary omega-3 fatty acids do not play a major role in protecting against asthma, and that higher levels of erythrocyte membrane linoleic acid are associated with a lower risk of asthma.

Topics: Adult; Asthma; Case-Control Studies; Dietary Fats, Unsaturated; Docosahexaenoic Acids; Eicosapentaenoic Acid; Erythrocyte Membrane; Fatty Acids; Fatty Acids, Omega-3; Female; Humans; Linoleic Acid; Male; Middle Aged; Risk

Electrospray ionization mass spectrometry was used to quantify phosphatidylcholine (PC) and phosphatidylglycerol (PG) molecular species in bronchoalveolar lavage fluid (BALF) from control and mild asthmatic subjects after local allergen challenge. BALF was obtained from 5 control and 13 asthmatic subjects before and 24 h after segmental allergen and saline challenge. There were no differences in the ratio of total PC to total PG or in the molecular species composition of PC or PG between the asthmatic and control groups under basal conditions. Allergen challenge in asthmatic but not in control volunteers caused a significant increase in the PC-to-PG ratio because of increased concentrations of PC species containing linoleic acid (16:0/18:2 PC, 18:0/18:2 PC, and 18:1/18:2 PC). These molecular species were characteristic of plasma PC analyzed from the same subjects, strongly suggesting that the altered PC composition in BALF in asthmatic subjects after allergen challenge was due to infiltration of plasma lipoprotein, not to catabolism of surfactant phospholipid. Interactions between surfactant and lipoprotein infiltrate may contribute to surfactant dysfunction and potentiate disease severity in asthma.

Topics: Allergens; Asthma; Bronchoalveolar Lavage Fluid; Humans; Linoleic Acid; Mass Spectrometry; Phosphatidylcholines; Phosphatidylglycerols; Reference Values

The proportions of linoleic acid in total plasma lipids and phospholipids were significantly greater and those of oleic acid were lower in pre-puberal and puberal atopic patients as compared with age-matched healthy controls. The n-3/n-6 fatty acid ratio of the triacylglycerol fraction was also lower in atopic patients. However, no significant decreases in the proportions of dihomo-gamma-linolenic acid and arachidonic acid were observed in plasma lipids of atopic patients, suggesting that delta 6-desaturase activity is not impaired in atopic patients. We provide an explanation for the beneficial effects of raising the n-3/n-6 ratio of dietary oils in the context of suppressing allergic hyper-reactivity in humans.

Topics: Adolescent; Asthma; Child; Dermatitis, Atopic; Fatty Acids; Fatty Acids, Omega-3; Humans; Linoleic Acid; Linoleic Acids; Lipids; Oleic Acid; Oleic Acids; Phospholipids; Triglycerides

Topics: Asthma; Free Radicals; Humans; Linoleic Acid; Linoleic Acids; Lipid Peroxidation

The beta-adrenergic receptor responsiveness of isolated guinea pig tracheal spirals can be negatively affected by intraperitoneal administration of the Gram-negative bacterium Haemophilus influenzae, four days prior to the experiment. The reduction in tracheal relaxation is accompanied by a decrease in beta-adrenergic receptor binding sites in splenic lymphocyte membranes and by a decrease in the fluidity of these membranes. The H. influenzae-induced dysfunction of both the respiratory airway and lymphocyte beta-adrenergic systems can be mimicked by modulating the amount of linoleic acid in the diet. This linoleic acid induced dysfunction of the beta-adrenergic system is also accompanied by a decrease in the plasma membrane fluidity of the splenic lymphocyte membranes of the guinea pigs. The role for plasma membrane fluidity in asthma is discussed in relation to current concepts for atopy.

Topics: Animals; Asthma; Dietary Fats; Guinea Pigs; Haemophilus influenzae; Immunization; Isoproterenol; Linoleic Acid; Linoleic Acids; Lymphocytes; Male; Membrane Fluidity; Random Allocation; Receptors, Adrenergic, beta; Spleen; Trachea